N-Acetylcysteine Treatment in Two Patients with Relapsed Thrombotic Thrombocytopenic Purpura Increased ADAMTS13 Activity, Free Thiol Concentration in Plasma, and Inhibited Platelet Activation

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a catastrophic and potentially fatal disorder caused by systemic microvascular thrombosis due to von Willebrand factor (VWF)-platelet thrombi. TTP is caused by congenital or acquired deficiency of the plasma metalloprotease ADAMTS13. Based on an earlier study (Chen J et al., J Clin Invest 2011, 121:593-603), we proposed N-acetylcysteine (NAC) as an adjunct treatment for TTP. This study showed that NAC reduced the size and activity of VWF in vitro in human plasma and in vivo in a TTP mouse model. In 2013 and 2014, two case reports described treatment of refractory TTP patients with NAC, one receiving a low dose of NAC [300 mg/kg (total 15 g) for the 1st 24 hrs, followed by 2.5 g/day for two weeks concurrently with plasma exchange] (Shortt J et al., N Engl J Med 2013, 368: 90-92; Shortt J et al., Transfusion 2014, 54:2362-2363) and the other receiving high-dose NAC [300 mg/kg/day (11 g/day) for 10 days between plasma exchanges] (Li GW et al. Transfusion 2014, 54: 1221-1224). The patient treated with high-dose NAC improved rapidly (the patient woke up from coma 18 hr after NAC treatment was initiated), but the patient treated with lower dose NAC did not appear to respond. Thus, it is as yet unclear whether NAC is an effective treatment for TTP. Therefore, more clinical studies and detailed analyses are required to examine the effects of NAC in TTP patients. Here we report the results of clinical and biochemical studies on two patients with relapsed TTP treated with NAC. Before, during, and after NAC treatment, we determined the concentrations of NAC, cysteine, and glutathione in plasma; VWF concentration, multimer structure, and functions; ADAMTS13 concentration and activity; and platelet counts and activation status (P-selectin expression and phosphatidylserine exposure). Methods: Two females with a history of prior episodes of TTP presented with acute TTP [ADAMTS13 < 10%, positive for ADAMTS13 inhibitors, platelet count ≤ 10,000/uL, lactate dehydrogenase (LDH) > 600 IU/L] and both were treated with NAC per IRB-approved protocol [150 mg/kg bolus over 1 hr and 150 mg/kg as continuous infusion until the next therapeutic plasma exchange (TPE)]. They received daily TPE until their platelet counts normalized, and intravenous NAC during days 2-5. Blood was collected daily for 8 days for research assays. ADAMTS13 concentrations in patient plasma were measured by ELISA. ADAMTS13 activity was measured using HRP-conjugated A2 peptide substrate (Wu J-J et al. J Thromb Haemost 2006, 4:129-136). Concentrations of NAC, total cysteine, and total free thiols (free thiol cysteine and free thiol NAC) in plasma were determined by mass spectrometry. Plasma VWF multimer patterns were analyzed by 1.5% agarose gel electrophoresis followed by western blotting with an HRP-conjugated polyclonal VWF antibody. Platelets in whole blood were labeled for platelet markers (CD41a or CD42b) together with one of the activation markers, P-selectin or phosphatidylserine (lactadherin). The labeled platelets were analyzed by flow cytometry. Results: Platelet counts in both patients started to increase 1 day after NAC infusion and continued to increase after discontinuation of NAC and TPE. After NAC infusion, the free thiol concentration (NAC and cysteine) in plasma increased 4 and 59 fold in patients 1 and 2, respectively. This was accompanied by increasing ADAMTS13 specific activity (ADAMTS13 activity/ADAMTS13 antigen). In patient 1, the specific activity increased from 127% (prior to NAC infusion but after TPE) to 270% during NAC infusion; in patient 2, the specific activity increased from 56% to 86%. In patient 1, the VWF multimer size decreased during NAC treatment and the VWF multimers migrated slightly faster. NAC also appeared to inhibit platelet activation. Before NAC infusion, the platelets in both patients were positive for phosphatidylserine (PS, > 30%) and P-selectin (> 15%), compared to 2% and 5%, respectively, in a normal control. The percentages of PS- and P-selectin-positive platelets decreased to less than 18% and 10% respectively, during NAC treatment. Summary: NAC treatment of two patients with TTP in conjunction with TPE was well tolerated and associated with recovery of platelet count and LDH, increased ADAMTS13 specific activity and total free thiol concentration in plasma, reduced platelet activation, and decreased VWF multimer size in one patient. Disclosures Konkle: CSL Behring: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Octapharma: Research Funding; Novo Nordisk: Consultancy.

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Platelet Counts Following Eltrombopag Discontinuation in Patients with Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.3517.3517 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3517-3517

Author(s):

Gregory Cheng ◽

Michael Tarantino ◽

Terry Gernsheimer ◽

Oliver Meyer ◽

Andres Brainsky ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenic Purpura ◽

Research Funding ◽

Rescue Medication ◽

Study Medication ◽

Bleeding Events ◽

Thrombocytopenic Purpura ◽

Baseline Platelet Count ◽

Platelet Counts ◽

Transient Decrease

Abstract Abstract 3517 Poster Board III-454 BACKGROUND Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA) is an oral, small molecule (565 Da), thrombopoietin receptor agonist that has been approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). It is also being studied in thrombocytopenic patients with chronic liver disease, hepatitis C, myelodysplastic syndromes, and cancer. Withdrawal of treatments that stimulate platelet production may theoretically result in recurrent thrombocytopenia below pretreatment levels (below baseline). OBJECTIVE: To determine whether worsening of thrombocytopenia (ie, platelet count decrease below baseline) occurs after discontinuation of eltrombopag in patients with chronic ITP. METHODS: The lowest median platelet counts during the first 4 weeks posttherapy were compared with median baseline platelet counts. Data from 369 patients treated in 3 randomized, double-blind, placebo-controlled studies were analyzed: TRA100773A and TRA100773B were 6-week studies, and RAISE was a 6-month study. For all 3 studies, a baseline platelet count <30,000/μL was required. Platelet counts, bleeding events, and the use of ITP medication were examined in the 4 weeks following the discontinuation of eltrombopag or placebo. A transient decrease in platelet counts (ie, worsening of thrombocytopenia) was defined as a platelet count below 10,000/μL and at least 10,000/μL below each patient's baseline platelet count (Bussel N Eng J Med 2006). RESULTS: Using pooled data from the 3 studies, no decreases below baseline median platelet counts (placebo, 16,300/μL; eltrombopag, 16,000/μL) were observed compared to the lowest median platelet counts within the first 4 weeks posttherapy (placebo, 14,000/μL; eltrombopag, 17,000/μL). Across the pooled studies, a total of 10/128 (8%) of placebo-treated patients and 20/241 (8%) of eltrombopag-treated patients had a transient decrease in platelet counts in the 4 weeks following discontinuation or interruption of treatment. None of the 10 placebo-treated patients had bleeding events associated with posttreatment platelet nadirs. Three of the 20 eltrombopag-treated patients had bleeding events and/or rescue treatment associated with the platelet nadir in the 4-week posttreatment period. One patient discontinued eltrombopag after achieving platelet counts >200,000/μL following on-therapy rescue medication (corticosteroid 0.5 mg/kg/day); 9 days after discontinuing study medication, the patient had grade 1 gum bleeding and resumed daily corticosteroids at an increased dose. The second patient had grade 3 menorrhagia and was administered vincristine (patient had a history of similar symptoms). The third patient had Henoch-Schoenlein purpura, interrupted eltrombopag due to platelet counts >400,000/μL, and 7 days after holding eltrombopag had a platelet count of 2000/μL, experienced grade 1 mouth hemorrhage and grade 2 petechiae, and did not require rescue medication. The patient continued in the study for the full 6 months and following permanent discontinuation of eltrombopag, this patient did not experience a transient decrease in platelet counts or any bleeding. CONCLUSION: Across 3 placebo-controlled studies, the incidence of transient decreases in platelet counts following discontinuation or interruption of study medication was similar in patients receiving eltrombopag or placebo. Therefore, these decreases may be unrelated to study medication and may represent normal fluctuations in platelet counts in patients with chronic ITP. Transient platelet count decreases were generally not associated with bleeding events. Disclosures: Cheng: GlaxoSmithKline: Research Funding. Tarantino:GlaxoSmithKline: Speakers Bureau; Lundbeck: Speakers Bureau; Baxter: Membership on an entity's Board of Directors or advisory committees. Gernsheimer:GlaxoSmithKline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Meyer:GlaxoSmithKline: Consultancy, Honoraria. Brainsky:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment.

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Association Of Platelet Function Markers, Independent Of Platelet Count, With Bleeding Score In Patients With Immune Thrombocytopenia

Blood ◽

10.1182/blood.v122.21.3534.3534 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3534-3534

Author(s):

Andrew L. Frelinger ◽

Anja J Gerrits ◽

Michelle A. Berny-Lang ◽

Travis Brown ◽

Sabrina L. Carmichael ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Platelet Function ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Univariate Analysis ◽

Blood Draw ◽

Platelet Surface ◽

Platelet Counts ◽

Bleeding Score

Abstract Background Immune thrombocytopenia (ITP) patients with similarly low platelet counts differ in their tendency to bleed. Aim To determine if differences in platelet function in ITP patients with similarly low platelet counts partly account for the variation in bleeding tendency. Methods The relationship between bleeding scores and platelet function markers was investigated in a single center cross-sectional study of pediatric patients with ITP. Following informed consent, blood was collected from ITP patients and bleeding was graded using the Buchanan and Adix Score (J Pediatr 2002) at routine clinic visits or while admitted to the hospital. Bleeding scores were obtained by one of three hematologists blinded to platelet function results, and investigators performing platelet function tests were blinded to clinical results. Platelet function was assessed by whole blood flow cytometric measurement of unstimulated, ADP- or TRAP-stimulated platelet surface activated GPIIb-IIIa (as measured by PAC1 binding), P-selectin, and GPIb and by unstimulated, convulxin-, or ADP plus TRAP-stimulated platelet surface phosphatidylserine expression (as determined by annexin V binding). Platelet count, immature platelet fraction (IPF) and mean platelet volume (MPV) were determined by a Sysmex XE-2100, and platelet forward angle light scatter (FSC) was measured by flow cytometry. Results Platelet function and bleeding scores were evaluated in 34 consecutive consenting pediatric ITP patients (16 female, 18 male, age 9.7 ± 5.7 years [mean ± SD]). ITP was newly diagnosed (< 3 months) in 10 patients, persistent (3 -- 12 months) in 7 patients, and chronic (>12 months) in 17 patients. Platelet count at the time of the blood draw was 47 ± 55 x 109/L. The median bleeding score on day of blood draw was 1 (range 0 to 4). By univariate analysis, higher IPF, and lower platelet count were significantly associated with a higher bleeding score (odds ratio [OR] >1, p<0.05) but MPV was not. Multiple measures of platelet function were associated with bleeding scores by univariate analysis: higher levels of platelet FSC (a measure affected by multiple variables including size) surface GPIb on unstimulated, ADP- or TRAP-stimulated platelets, surface P-selectin on unstimulated platelets, and platelet FSC were associated with increased odds for higher bleeding scores (ORs each >1, p<0.05), while higher ADP- and TRAP-stimulated platelet surface activated GPIIb-IIIa and P-selectin were associated with reduced odds of higher bleeding scores (ORs each <1, p<0.05). After adjustment for platelet count, higher levels of platelet surface P-selectin on unstimulated platelets, GPIb on TRAP-stimulated platelets, and FSC remained significantly associated with increased odds for higher bleeding scores (Figure), but IPF did not. Similarly, after adjustment for platelet count, higher TRAP-stimulated percentage of P-selectin and activated GPIIb-IIIa positive platelets remained significantly associated with reduced odds of higher bleeding scores (Figure). These findings were independent of recent ITP-related treatment. Conclusions In this study of pediatric ITP patients, we identified selected platelet function markers which, independent of platelet count, are associated with increased (platelet FSC, platelet surface P-selectin on unstimulated platelets, and GPIb on TRAP-stimulated platelets) or decreased (TRAP-stimulated percent P-selectin and GPIIb-IIIa positive platelets) odds of high bleeding scores. Possible hypotheses to explain these associations are as follows: 1) Increased P-selectin on unstimulated platelets demonstrates in vivo platelet activation, possibly as a consequence of the recent bleeding. 2) Because platelet activation results in a reduction in platelet surface GPIb and increases in platelet surface activated GPIIb-IIIa and P-selectin, the ORs associated with all of these markers could be explained by reduced ability of platelets in patients with higher bleeding scores to respond to agonists. 3) While platelet FSC is partly related to size, the finding that MPV and IPF, adjusted for platelet count, were not associated with bleeding score suggests that factors other than size account for the association of platelet FSC with higher bleeding scores. Further study is required to validate these findings and determine if differences in platelet function are associated with future risk for bleeding. Disclosures: Off Label Use: Eltrombopag was given to WAS/XLT patients for treatment of thrombocytopenia. Neufeld:Shire: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Apopharma: Consultancy. Michelson:Sysmex: Honoraria.

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Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin

Blood ◽

10.1182/blood.v82.5.1415.bloodjournal8251415 ◽

1993 ◽

Vol 82 (5) ◽

pp. 1415-1421 ◽

Cited By ~ 79

Author(s):

B Godeau ◽

S Lesage ◽

M Divine ◽

V Wirquin ◽

JP Farcet ◽

...

Keyword(s):

Body Weight ◽

Platelet Count ◽

Treatment Protocol ◽

Complete Response ◽

Long Term Results ◽

High Dose ◽

Thrombocytopenic Purpura ◽

Autoimmune Thrombocytopenic Purpura ◽

Platelet Counts

Intravenous (i.v.) infusions of Ig concentrates are an effective but expensive treatment for patients with autoimmune thrombocytopenic purpura (AITP). The optimal treatment protocol and the long-term results are uncertain, and the precise mechanism by which the platelet count increases is poorly understood. Twenty adult patients with chronic AITP were enrolled in a prospective study to compare the respective efficacy of two high-dose IVIgG induction regimens (1 g v 2 g/kg body weight) and the long-term effect of six 1 g/kg body weight i.v. IgG reinfusions. An initial response was observed in all 18 evaluable patients: the platelet count increased to a mean value of 251 x 10(9)/L (range 72 to 836 x 10(9)/L) and the mean pretreatment platelet count was multiplied by 14.6. No difference in efficiency was observed between the two i.v. IgG dosages. The degree of the platelet count increment correlated in both groups with the increase in the clearance of antibody-coated red blood cells, measured by an isotopic method, but not with the serum IgG elevation. Treatment was considered to have failed in 11 patients, 90 days after the last i.v. IgG reinfusion (D90), because the platelet counts were comparable with pretreatment values. In contrast, a complete response was observed at D90 in five patients (mean platelet count: 184 x 10(9)/L; range: 150 to 250 x 10(9)/L) and a partial response at D90 was obtained in the remaining two patients (platelet counts: 70 and 104 x 10(9)/L). Five of the 7 responders at D90 kept a platelet count above 50 x 10(9)/L during the entire follow-up period (mean 33 months; range: 5 to 66) with no further treatment; unfortunately, no clinical or biologic criteria were found to be predictive of the long-term response. This study shows that an i.v. IgG infusion regimen of 1 g/kg body weight could safely replace the classical 2 g/kg body weight dosage, at least in patients who do not have life-threatening thrombocytopenia. Moreover, repeated i.v. IgG reinfusion could be an alternative for AITP patients in whom splenectomy is contraindicated.

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Treatment of adult chronic autoimmune thrombocytopenic purpura with repeated high-dose intravenous immunoglobulin

Blood ◽

10.1182/blood.v82.5.1415.1415 ◽

1993 ◽

Vol 82 (5) ◽

pp. 1415-1421 ◽

Cited By ~ 5

Author(s):

B Godeau ◽

S Lesage ◽

M Divine ◽

V Wirquin ◽

JP Farcet ◽

...

Keyword(s):

Body Weight ◽

Platelet Count ◽

Treatment Protocol ◽

Complete Response ◽

Long Term Results ◽

High Dose ◽

Thrombocytopenic Purpura ◽

Autoimmune Thrombocytopenic Purpura ◽

Platelet Counts

Abstract Intravenous (i.v.) infusions of Ig concentrates are an effective but expensive treatment for patients with autoimmune thrombocytopenic purpura (AITP). The optimal treatment protocol and the long-term results are uncertain, and the precise mechanism by which the platelet count increases is poorly understood. Twenty adult patients with chronic AITP were enrolled in a prospective study to compare the respective efficacy of two high-dose IVIgG induction regimens (1 g v 2 g/kg body weight) and the long-term effect of six 1 g/kg body weight i.v. IgG reinfusions. An initial response was observed in all 18 evaluable patients: the platelet count increased to a mean value of 251 x 10(9)/L (range 72 to 836 x 10(9)/L) and the mean pretreatment platelet count was multiplied by 14.6. No difference in efficiency was observed between the two i.v. IgG dosages. The degree of the platelet count increment correlated in both groups with the increase in the clearance of antibody-coated red blood cells, measured by an isotopic method, but not with the serum IgG elevation. Treatment was considered to have failed in 11 patients, 90 days after the last i.v. IgG reinfusion (D90), because the platelet counts were comparable with pretreatment values. In contrast, a complete response was observed at D90 in five patients (mean platelet count: 184 x 10(9)/L; range: 150 to 250 x 10(9)/L) and a partial response at D90 was obtained in the remaining two patients (platelet counts: 70 and 104 x 10(9)/L). Five of the 7 responders at D90 kept a platelet count above 50 x 10(9)/L during the entire follow-up period (mean 33 months; range: 5 to 66) with no further treatment; unfortunately, no clinical or biologic criteria were found to be predictive of the long-term response. This study shows that an i.v. IgG infusion regimen of 1 g/kg body weight could safely replace the classical 2 g/kg body weight dosage, at least in patients who do not have life-threatening thrombocytopenia. Moreover, repeated i.v. IgG reinfusion could be an alternative for AITP patients in whom splenectomy is contraindicated.

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Thromboembolic Events Observed in Eltrombopag Clinical Trials in Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.2423.2423 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2423-2423 ◽

Cited By ~ 8

Author(s):

James B. Bussel ◽

Gregory Cheng ◽

Mansoor N. Saleh ◽

Sandra Vasey ◽

Manuel Aivado ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Study Medication ◽

Normal Range ◽

Advisory Committees ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Equity Ownership

Abstract Abstract 2423 Poster Board II-400 BACKGROUND: Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA), an oral, small molecule, thrombopoietin receptor agonist, was recently approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). Limited published data indicate that patients with chronic ITP experience thromboembolic events (TEEs) with a frequency of 3% to 6%. (Aledort, Am J Hematol, 2004; Bennett, Haematologica, 2008). OBJECTIVE: To evaluate the incidence of TEEs in patients with chronic ITP treated with eltrombopag and to determine if the occurrence of TEEs was associated with elevated platelet counts. METHODS: Data from 446 patients from 3 placebo-controlled eltrombopag studies (TRA100773A, TRA100773B, and RAISE) and 2 open-label studies (REPEAT and EXTEND) were analyzed. The frequency of TEEs or suspected TEEs before and after the first dose of study medication (placebo or eltrombopag) was examined across the program. Potential risk factors, including platelet counts proximal to the event, were evaluated in patients experiencing a TEE. RESULTS: Prior to the initiation of study medication (placebo or eltrombopag), 16/493 (3.2%) of the patients entering the program had a history of TEEs (one of these patients experienced 2 additional TEEs [TIA, MI] while on treatment with eltrombopag). Across the ITP clinical program, 17/446 patients treated with eltrombopag (3.8%) experienced 22 TEEs. No patient treated with placebo experienced a TEE. The patient-years (PYs) of exposure to study medication was approximately 14 times greater for patients treated with eltrombopag compared to placebo (eltrombopag 377 PYs; placebo 26 PYs). Most patients (13/17) experienced 1 TEE; 3 patients experienced 2, and 1 patient experienced 3 (2 TEEs were 6 months off-therapy). The most common TEEs were deep vein thrombosis (n=8) and pulmonary embolism (n=6). A total of 18/22 events were resolved or resolving at the time of this analysis; all patients experiencing a TEE had at least 1 risk factor for these events other than ITP (eg, use of IVIg [n=3], hospitalization with no prophylactic anticoagulation [n=4], oral corticosteroids [n=6]). The platelet counts proximal to the event ranged from 14,000/μL to 420,000/μL. The majority of patients had platelet counts below 150,000/μL (9; 53%) or between 150,000/μL and 400,000/μL (5; 29%); 2 had platelet counts above 400,000/μL and the platelet count in 1 was unknown. All 446 patients were categorized by the maximum platelet count achieved during treatment with eltrombopag (above normal [>400,000/μL], normal range [150–400,000/μL], below normal range [<150,000/μ]; Table 1). The majority of patients (14; 82%) experienced the TEEs at a platelet count lower than their maximum platelet count, while 3 patients (18%) experienced a TEE proximal to their maximum platelet count. CONCLUSION: TEEs occurred with eltrombopag. None occurred with placebo; however, the PYs of exposure was considerably less with placebo than with eltrombopag. The frequency of TEEs observed during eltrombopag treatment (3.8%) is similar to that reported in the literature and prior to enrollment in the eltrombopag program (3.2%). No discernible correlation has been observed between platelet count increases and TEEs, and these events do not appear to be associated with maximum platelet counts during treatment with eltrombopag. Disclosures: Bussel: Sysmex: Research Funding; Eisai, Inc: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees. Cheng:GlaxoSmithKline: Research Funding. Saleh:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau. Vasey:GlaxoSmithKline: Employment. Aivado:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

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Relapsing Thrombotic Thrombocytopenic Purpura: A Single Center Experience

Blood ◽

10.1182/blood.v128.22.3732.3732 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3732-3732

Author(s):

Arielle L Heeke ◽

Craig M. Kessler ◽

Catherine Broome

Keyword(s):

Disease Control ◽

Thrombotic Thrombocytopenic Purpura ◽

Research Funding ◽

Activity Level ◽

High Dose ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

The Mean ◽

Term Management

Abstract Thrombotic thrombocytopenic purpura (TTP) is due to a severe deficiency of the von Willebrand factor (vWF) cleaving serine metalloprotease ADAMTS13 and is most commonly diagnosed in adults due to autoantibodies against ADAMTS13. Standard therapy includes plasma exchange (PEX) until platelet counts normalize plus concurrent high dose corticosteroids. In refractory cases, weekly pulse Rituximab for 4 doses is often added. Successful long-term management of relapsing patients beyond these treatments is unclear, in part because the mechanisms for relapsing TTP are unknown. Dysfunctional immunoregulatory systems likely play a role in relapsing disease. Several case series have described disease control following bortezomib therapy (Patriquin 2016). Other immunomodulators including complement pathway and tyrosine kinase inhibitors may prove to offer benefit. Further, supplementing PEX with N-acetylcysteine (Rottenstreich 2016) & Caplacizumab (anti-vWF humanized immunoglobulin) (Peyvandi 2016) has shown promising preliminary clinical results when used to treat an acute episode. Effects on relapse rates with these treatments have not been fully evaluated. Eight cases of relapsing TTP were identified at MedStar Georgetown University Hospital May 2004 to July 2016. Relapsing TTP was defined as recurrent episode(s) of thrombocytopenia, microangiopathic hemolysis, and confirmed ADAMTS13 activity levels <10% following remission from the initial TTP episode. Retrospective chart review was completed to evaluate demographic and clinicopathologic features, laboratories and treatment at relapse(s), and clinical outcomes. In our 8 patient cohort, 75% are female (6/8), 62.5% are African American (AA) (5/8), and the mean age at initial TTP diagnosis is 35.38 (range 16-67). The mean number of relapses is 3.38 (range 2-9) with a mean platelet nadir of 45,000/mcL. All patients remain alive. Two are ANA positive, 1 with known systemic lupus erythematosus (SLE) and 1 with suspected SLE. None are HIV positive, and none endorse a family history of TTP. Four identified infections as triggers for their TTP, 1 patient developed TTP during pregnancy and hormonal fertility treatments, and 3 had no identifiable triggers. All had an increased titer of ADAMTS13 inhibitor (Bethesda titer range 0.7 - >8) at the time of relapse(s). Normalization of ADAMTS13 activity was confirmed in most following treatment (n=6), with a mean ADAMTS13 activity level between relapses of 50.5% (range 32-88%). At the time of each relapse, all patients underwent daily PEX with fresh frozen plasma plus high dose corticosteroids for at least 5 days (range 5-21 days), with some requiring gradual PEX weaning over 1-4 weeks and steroid tapering over months based on lab parameters. Two relapsed quickly after PEX discontinuation, both in the setting of systemic illness (lupus flare, cholecystitis). Sequelae of TTP (neurologic, renal, hematologic anomalies) resolved with treatment. All patients received Rituximab therapy during the 1st or 2nd relapse. For the majority (87.5%, 7/8), this intervention did not lead to long-term remission, although 100% (2/2) who transitioned to prophylactic bolus Rituximab every 6 months post splenectomy achieved long-term disease control. It is difficult to distinguish whether remission resulted from maintenance Rituximab, the splenectomy, or a combination of the two. Patients who underwent splenectomy were vaccinated and have not had difficulty with infections or thrombosis. In conclusion, our cohort of patients with relapsing TTP all had documented ADAMTS13 inhibitors and acutely responded to daily PEX (most requiring PEX wean based on lab parameters) plus high dose corticosteroids. Although Rituximab therapy during initial relapse did not offer a high percentage of long-term remissions, the addition of prophylactic Rituximab every 6 months post splenectomy has achieved long-term control in 2 patients. In our cohort the majority are AA, suggesting genetic susceptibility. HLA/immune transcript levels and ribosomal gene signatures may correlate with TTP disease activity and risk for relapse (Edgar 2015), and could be used to identify high-risk patients in need of more intensive therapy. Given the complexity and severity of this disease, there is an ongoing need for evaluation of relapsing TTP and best strategies for long-term management. Disclosures Kessler: Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Pfizer: Consultancy; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Broome:True North Therapeutics: Honoraria; Alexion Pharmaceuricals: Honoraria.

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Rituximab Is Effective in Refractory Adult Immune Thrombocytopenic Purpura Associated with Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v104.11.3952.3952 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3952-3952

Author(s):

Thein H. Oo ◽

Neela Natarajan

Keyword(s):

Platelet Count ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Immune Thrombocytopenic Purpura ◽

Peripheral Blood ◽

Lymphocytic Leukemia ◽

High Dose ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Refractory Itp

Abstract Chronic lymphocytic leukemia ( CLL ) is the commonest leukemia in the western world. 2% of CLL patients present with immune thrombocytopenic purpura ( ITP ). Corticosteroids, intravenous immune globulins ( IVIG ) and splenectomy have been the mainstay of treatment of ITP. Rituximab is the monoclonal antibody against CD-20 antigen expressed on the B-lymphocytes. It has established its role in the treatment of many B-cell malignancies in the last one decade. Due to its B-cell depletion capability, interests in employing rituximab in the treatment of many autoimmune diseases have grown in the last few years. Recently, many small case reports/series and a few small trials have reported the efficacy of rituximab in the treatment of refractory ITP. However, not much is known about its efficacy in the ITP associated with CLL. Here, a patient with CLL initially presenting with ITP is described. A 67-year-old white female with a past history of hysterectomy for fibroids and hypertension presented with rectal bleeding and multiple ecchymoses. Physical examination was unremarkable except for skin eccymoses on the extremities and abdomen. Colonscopy revealed hemorrhoids only. Computerized tomograms showed no lymphadenopathy or other abnormalities. Here laboratory data were as follows; hemoglobin 5.8g/dl, WBC 29,400/mm3, platelet 13,000/mm3, lymphocyte 52%, neutrophil 45%, monocyte 2.5%. Chemistry profile was unremarkable. Her blood group was O, Rh-negative. She was initially treated at another institution with packed Red Blood Cells, prednisone 1.5mg/kg qd and daily IVIG 0.4g/kg for 5 days for presumed ITP. Platelet transfusions did not raise the platelet counts. She remained profoundly thrombocytopenic and was subsequently transferred to our hospital. Review of the blood smear revealed anisopoikilocytosis, few tear-drop RBCs, many small-to-medium sized mature lymphocytes, occasional smudge cells, large platelets, few Pseudo-Pelgar-Huet cells but no blasts. Given moderate absolute lymphocytosis ( 15,200/mm3 ), blood film findings and profound thrombocytopenia, a working diagnosis of CLL-associated ITP was entertained. Peripheral blood flow cytometry showed lymphocytes positive for CD5, CD19, CD20 (dim ) and CD23, kappa/lambda ratio of 248:1. Bone marrow biopsy showed moderate lymphocytosis with the same immunophenotype as peripheral blood. Megakaryocytes were abundant. The diagnosis was confirmed. She was treated with a course of high dose methylprednisone, 2 courses of IVIG 1g/kg x 2days with very transient response. Due to this, she underwent splenectomy but her platelet counts remained low. She required another 5 courses of IVIG resulting in brief responses over the next 3 weeks. She was subsequently put on po danazol 200mg bid with short-lived responses. Eventually, she received iv rituximab 375mg/m2 weekly for 4 weeks. She achieved complete remission within 1 month. Two months later, she transferred her care to another facility. Review of the literature showed 1 case report of CLL-associated refractory ITP successfully treated with rituximab and the response duration was 6 months. Three CLL patients with refractory fludarabine-associated ITP also responded to rituximab. Of them, two achieved a platelet count over 100,000/mm3 and 1 achieved a platelet count of 72,000/mm3 within 4 weeks. Duration of responses ranged from 6 to 17 months. Those results together with our case suggest rituximab is an alternative agent for the treatment of CLL-associated ITP. Its potential in ITP associated with B-cell lymphoid malignancies should be explored further.

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Severe Immune Thrombocytopenic Purpura Treated with Plasma Exchange

Kathmandu University Medical Journal ◽

10.3126/kumj.v10i1.6922 ◽

2012 ◽

Vol 10 (1) ◽

pp. 77-82 ◽

Cited By ~ 4

Author(s):

MR Sigdel ◽

DS Shah ◽

MP Kafle ◽

KB Raut

Keyword(s):

Platelet Count ◽

Plasma Exchange ◽

Immune Thrombocytopenic Purpura ◽

Low Dose ◽

High Dose ◽

Severe Thrombocytopenia ◽

First Line ◽

Thrombocytopenic Purpura ◽

Steroid Resistant ◽

Low Platelet Count

Immune thrombocytopenic purpura (ITP) is a hematological disorder characterized by immunologically mediated destruction of platelets and absence of other causes of thrombocytopenia. Treatment is required when the low platelet count entails risk of serious bleeding. Steroid is the first line of management. Acute refractory ITP with very low platelet count is variably treated with high dose steroid, intravenous immunoglobulin (IVIg), anti D or emergency splenectomy. Here, we present a case of steroid resistant ITP with severe thrombocytopenia treated with plasma exchange and low dose IVIg who responded dramatically to the therapy with maintained platelet count till one month from the institution of therapy. KATHMANDU UNIVERSITY MEDICAL JOURNAL VOL.10 | NO. 1 | ISSUE 37 | JAN - MAR 2012 | 85-87 DOI: http://dx.doi.org/10.3126/kumj.v10i1.6922

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Second Generation Direct-Acting Antiviral Agents Eradicate Hepatitis C Virus (HCV) but Exacerbate Thrombocytopenia in a Patient with HCV-Associated Immune Thrombocytopenic Purpura (ITP): Case Report

Blood ◽

10.1182/blood.v124.21.5022.5022 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5022-5022

Author(s):

Le Min Lee ◽

Max E Johansen ◽

Wenche Jy ◽

Lawrence L Horstman ◽

Yeon-Soong Ahn

Keyword(s):

Platelet Count ◽

Hepatitis C ◽

Autoimmune Diseases ◽

Acute Exacerbation ◽

Second Generation ◽

Hcv Infection ◽

High Dose ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Dose Prednisone

Abstract Background Lymphotropism of HCV induces chronic immune stimulation, facilitating production of wide variety of autoantibodies, leading to HCV driven autoimmunity. Immune thrombocytopenic purpura (ITP) is one of extra hepatic manifestations of autoimmune diseases in HCV infection. The treatment landscape of hepatitis C virus infection has been dramatically altered in 2013 with the approvals of the second-generation protease inhibitor simeprevir and the nucleotide polymerase inhibitor sofosbuvir. In most patients treated with the direct-acting antiviral agent (DAA), HCV RNA became undetectable. However a little is known about how DAA therapy affects autoimmune diseases associated with HCV, especially in ITP. Cessation of immune stimulation by HCV following the treatment may alter immune responses and may modify autoimmune diseases. We report here a case of acute exacerbation of ITP following DAA treatment. DAA therapy appears to precipitate acute exacerbation of thrombocytopenia and ITP became refractory to all treatments including the measures that used to induce remission prior to DAA treatment. Case report A 67-year-old man was diagnosed chronic HCV infection, genotype 1b, in 1997. He failed treatment with Interferons. Chronic active hepatitis subsequently progressed into cirrhosis with portal hypertension. His ITP required frequent treatments with Prednisone and IVIG. It became severe in early 2013. His platelet counts were low at 10,000. He responded well to high dose Prednisone but could not continue because of worsening diabetes. He also failed Rituxan. He received multiple treatments including eltrombopag and romiplostin which he did not respond well to. His ITP finally stabilized with monthly infusion of WinRho as maintenance therapy with platelet counts hovering around 40.000 for 6 months. In March 2014, he was started on HCV treatment with simeprevir, sofosbuvir and ribavirin. His baseline platelet count prior to the new treatment was in the 50000’s. It plummeted to below 10.000 two weeks into treatment. He developed multiple ecchymosis and blood blisters in the mouth. He completed his HCV treatment on June 3, 2014. His viral load was no longer detectable. However, ITP remained refractory and severe with platelet counts around 10,000. High dose Prednisone or WinRho which had been effective in raising platelet counts previously were no longer effective after DAA therapy. During this acute exacerbation of ITP, he was treated with IVIG 3 times a week and low dose Prednisone and NPlate weekly with increasing dosage. He developed frequent blood blisters in mouth and gum bleeding requiring emergency room visits and hospitalization where he received platelet transfusions along with IVIGG and high dose Prednisone. His hemoglobin was stable throughout. IVIGG was reduced to 2 times a week. At 8 weeks following completion of DAAs, his platelet count improved to 40.000s range without clinical sign of bleeding. Discussion It has been shown that the frequency of B-cell production of anti- GPIIb-IIIa antibody, an antibody against the major platelet surface autoantigen (BP IIb-IIIa) recognized by anti-platelet antibodies in patients with idiopathic thrombocytopenic purpura (ITP), was greater in HCV-ITP (9). An inverse correlation was found between platelet count and B-cell anti–GPIIb-IIIa Ab production in 51 patients with liver cirrhosis (73% with hepatitis C). In our patient, ITP was stable with maintenance infusion of WinRho for 6 months. Acute exacerbation of ITP 2 weeks into DAA therapy suggests that it was triggered by the DAAs. Thrombocytopenia is a well-recognized complication of interferon therapy for treatment of viral hepatitis. Simeprevir and sofosbuvir however, are not well known to affect the platelet count. A little is known on effect of DAAs on thrombocytopenia. Immune alteration following eradication of HCV and subsequent modification of autoimmunity could affect course of ITP associated with HCV infection. Meanwhile, it is important for physicians and patients to be aware of potentially dangerous complications of these second generation DAAs. Disclosures No relevant conflicts of interest to declare.

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A Phase II Study To Assess the Safety, Efficacy and Tolerability of Rituximab in Combination with Plasma Exchange in Patients with Acute Idiopathic Thrombotic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v110.11.1303.1303 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1303-1303

Author(s):

Marie Scully ◽

Jamie Cavenagh ◽

Beverley Hunt ◽

Hannah Cohen ◽

Samuel J. Machin

Keyword(s):

Platelet Count ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Phase Ii ◽

Trial Group ◽

Normal Range ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Historical Group ◽

Historical Controls

Abstract This multi-centre, phase II non-randomised trial, using Rituximab, in conjunction with standard therapy, plasma exchange (PEX) and pulsed methylprednisolone (MP), to include 40 adult patients with acute idiopathic thrombotic thrombocytopenic purpura (TTP). Rituximab 375mg/m2 was given once a week for 4 weeks, following plasma exchange, started within 3 days of admission, having excluded secondary TTP causes such as pregnancy/retroviral infection. ADAMTS 13 activity/IgG antibody levels guided further therapy to a maximum of 8 treatments. Historical cases were used as comparisons to determine if Rituximab therapy on admission was associated with improved time to remission, defined by platelet count and number of PEX. Secondary outcomes were relapse rate, mortality at 3 months, safety/toxicity of Rituximab, effect on B-lymphocytes, ADAMTS 13 activity and IgG antibodies to ADAMTS 13. Results from the first 20 patients (15 females and 5 males), median age 43 years with 5 females presenting with an acute relapse TTP, none previously receiving Rituximab. All received 4 weekly Rituximab treatments and 2 continued to 8. Eight were afro-Caribbean (A/C), 9 Caucasian and 3 SE Asian. Historical controls: 17 females and 3 males, 5 with relapsed acute TTP, median age 42 years. 14 were Caucasian, 5 A/C and 1 Asian. There were comparable presenting features in both groups. The median number of PEX to remission in the trial group was 13.5 and 19 in the historical group. Platelet counts on admission were 12 (8–31) x109/L for trial cases and 14 (4–78) x109/L in historical controls. Pre 1st Rituximab therapy, median platelet count was 23x 109/L. By day 7 platelet counts were 211 x109/L for the historic controls but 9/20 had platelets< 150 x109/L. Pre 2nd Rituximab (day 8) for trial cases, median platelet counts were 91 x109/L and 10/20 had platelets <150x109/L. However, by day 15 (pre 3rd Rituximab) median platelet counts were 228 x109/L and was sustained. In the trial group, 2 patients received other immunosuppressive therapies (vincristine in 2 and ciclosporin (CSA) in 1). In the historical group, 5 received CSA, 4 defibrotide, 2 cyclophosphamide and 4 vincristine. In both groups, median ADAMTS 13 activity was <5% on admission. In the Rituximab cases, activity was 33% at 4 weeks and 51% at 3 months (normal range >66%). Median IgG ADAMTS 13 on admission was 34% (7–162%), reducing to a median of 9% pre the 4th Rituximab (normal range <4.2%). CD19 pre 1st Rituximab was 31% and pre 2nd, 4.5% (normal range 5–15%); specifically, there have been no increased infectious episodes. There was no deaths or serious adverse events in the patients receiving Rituximab. One patient in the historical group died. There have been no relapses in the trial group, follow-up 3–15 months. Over 15 months in the historical group, 10/20 had relapsed. In conclusion, Rituximab appears to be safe in patients with acute idiopathic TTP. The trial group have a greater proportion of A/C cases with a trend for more PEX to remission. However the trial group have had no episodes of relapse compared to the historical group, in which 50% of patients had further TTP episodes.

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